Novel target genes of the yeast regulator Pdr1p: a contribution of the TPO1 gene in resistance to quinidine and other drugs

Matta, Maria Adelaide do Valle; Jonniaux, Jean-Luc; Balzi, Elisabetta; Goffeau, André; Hazel, Bart van den

doi:10.1016/s0378-1119(01)00558-3

Cited by 50 publications

(41 citation statements)

References 29 publications

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“…This ePDR includes the up-regulation of PDR5, SNQ2, YOR1, TPO1, YLR346c, VHR1, and ICT1. It could potentially be adapted to many different toxic conditions, as it involves four transporters for broad, complementary, but overlapping drug spectra (51,52). This ePDR is induced as rapidly as the fluphenazine-and benomyl-specific responses, i.e.…”

Section: Discussionmentioning

confidence: 99%

The Central Role of PDR1 in the Foundation of Yeast Drug Resistance

Fardeau

Lelandais

Oldfield

et al. 2007

Journal of Biological Chemistry

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The widespread pleiotropic drug resistance (PDR) phenomenon is well described as the long term selection of genetic variants expressing constitutively high levels of membrane transporters involved in drug efflux. However, the transcriptional cascades leading to the PDR phenotype in wild-type cells are largely unknown, and the first steps of this phenomenon are poorly understood. We investigated the transcriptional mechanisms underlying the establishment of an efficient PDR response in budding yeast. We show that within a few minutes of drug sensing yeast elicits an effective PDR response, involving tens of PDR genes. This early PDR response (ePDR) is highly dependent on the Pdr1p transcription factor, which is also one of the major genetic determinants of long term PDR acquisition. The activity of Pdr1p in early drug response is not drug-specific, as two chemically unrelated drugs, benomyl and fluphenazine, elicit identical, Pdr1p-dependent, ePDR patterns. Our data also demonstrate that Pdr1p is an original stress response factor, the DNA binding properties of which do not depend on the presence of drugs. Thus, Pdr1p is a promoter-resident regulator involved in both basal expression and rapid drug-dependent induction of PDR genes.All living organisms have developed complex transcriptional responses for rapidly adapting genome expression to the presence of toxic compounds in the environment. These responses involve various types of cellular pathway. Genome-wide studies of drug responses in microorganisms have revealed that these responses comprise both specific effects depending on the precise chemical nature and cellular targets of the toxic compound and a general stress response (environmental stress response (ESR) 5 in the yeast Saccharomyces cerevisiae), reflecting cell adaptation to growth defects and cellular damages, regardless of the type of stress encountered by the cell (1). Inbetween these very specific and very general responses, prokaryotic and eukaryotic cells have evolved multidrug resistance (MDR) pathways, which confer resistance to a broad spectrum of unrelated chemicals, but which are restricted to the stress responses associated with organic drugs. From bacteria to humans, MDR is essentially based on the overexpression of membrane transporters able to export a large number of chemically different compounds (2-4). MDR is a major concern for human health, as it leads to antibiotic resistance in pathogens and enables cancer cells to survive chemotherapy.In the model yeast S. cerevisiae, MDR is referred to as PDR (pleiotropic drug response). The PDR network currently comprise 10 transcription factors regulating about 70 different target genes reviewed in Ref. 18). In this network, the Pdr1p transcription factor has the largest set of potential targets (about 50). Pdr1p and its functional homologue, Pdr3p, were identified in the early 1990s as regulators of the basal level of drug resistance in yeast cells (19,20). Gain-or loss-of-function alleles of PDR1 and PDR3 confer resistance or sensitivit...

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Section: Discussionmentioning

confidence: 99%

The Central Role of PDR1 in the Foundation of Yeast Drug Resistance

Fardeau

Lelandais

Oldfield

et al. 2007

Journal of Biological Chemistry

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Section: Introductionmentioning

confidence: 99%

“…Among these transporters, four members of the DHA1 family of MFS-MDR transporters, Tpo1, Tpo2, Tpo3 and Tpo4, have been described as polyamine exporters (Albertsen et al, 2003;Tomitori et al, 1999 Tomitori et al, , 2001Uemura et al, 2005). The best characterized of these four polyamine resistance transporters, Tpo1, has also been related to the extrusion of the antimalarial drugs quinidine (do Valle Matta et al, 2001) and artesunate and the herbicide 2,4-dichlorophenoxyacetic acid .During this work, we identified that Qdr3 is a determinant of resistance to spermine and spermidine, but not to putrescine. The effect of polyamine stress exposure or nitrogen limitation on the increase of QDR3 transcript levels was assessed, and Yap1 and Gcn4 were identified as the transcriptional regulators controlling QDR3 up-shift.…”

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Yeast response and tolerance to polyamine toxicity involving the drug : H+ antiporter Qdr3 and the transcription factors Yap1 and Gcn4

et al. 2011

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The yeast QDR3 gene encodes a plasma membrane drug : H + antiporter of the DHA1 family that was described as conferring resistance against the drugs quinidine, cisplatin and bleomycin and the herbicide barban, similar to its close homologue QDR2. In this work, a new physiological role for Qdr3 in polyamine homeostasis is proposed. QDR3 is shown to confer resistance to the polyamines spermine and spermidine, but, unlike Qdr2, also a determinant of resistance to polyamines, Qdr3 has no apparent role in K + homeostasis. QDR3 transcription is upregulated in yeast cells exposed to spermine or spermidine dependent on the transcription factors Gcn4, which controls amino acid homeostasis, and Yap1, the main regulator of oxidative stress response. Yap1 was found to be a major determinant of polyamine stress resistance in yeast and is accumulated in the nucleus of yeast cells exposed to spermidine-induced stress. QDR3 transcript levels were also found to increase under nitrogen or amino acid limitation; this regulation is also dependent on Gcn4. Consistent with the concept that Qdr3 plays a role in polyamine homeostasis, QDR3 expression was found to decrease the intracellular accumulation of [ 3 H]spermidine, playing a role in the maintenance of the plasma membrane potential in spermidine-stressed cells. INTRODUCTIONMultidrug efflux transporters are found in all living cells and are thought to recognize a wide variety of structurally and pharmacologically unrelated drugs. They are proposed to actively extrude or compartmentalize drugs and other xenobiotics, thus providing protection from these compounds (Jungwirth & Kuchler, 2006;Paulsen, 2003;Prasad et al., 2002;Roepe et al., 1996;. The activity of these proteins underlies the manifestation of cellular drug resistance, seriously limiting the therapeutic potential of drugs (Hayes & Wolf, 1997). The in silico analysis of the yeast genome revealed the existence of 23 putative drug : H + antiporters of the multiple drug resistance (MDR) family of the major facilitator superfamily (MFS). Although many of these proteins have been shown to confer resistance to a wide variety of drugs and chemicals (Paulsen et al., 1998;, the molecular mechanisms behind their apparent promiscuity remain elusive and a topic of debate (Jungwirth & Kuchler, 2006;Paulsen, 2003;Prasad et al., 2002;Roepe et al., 1996;.In the present work, we have further examined the biological function of the MFS-MDR transporter encoded by the QDR3 gene, which is present in the plasma membrane of Saccharomyces cerevisiae (Huh et al., 2003;Tenreiro et al., 2005). Qdr3 belongs to cluster I of the DHA1 drug efflux family, including putative drug : H + antiporters with 12 predicted membrane-spanning segments (Paulsen et al., 1998), and confers yeast resistance against the antiarrhythmic and antimalarial drug quinidine, the herbicide barban and the antitumour agents bleomycin and cisplatin (Tenreiro et al., 2005). Through genome-wide screenings, QDR3 gene deletion was also found to increase yeast susceptibility towards ma...

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“…Qdr2p confers yeast resistance against the antiarrhythmic and antimalarial drug quinidine, the herbicide barban, and the antitumour agents bleomycin and cisplatin (45,47). Remarkably, at least six other members of the DHA12 family of S. cerevisiae drug:H ϩ antiporters, belonging to the same cluster I or to cluster II, are individually required for quinidine resistance (8,9,10,27,44,45). Together with the stereoisomer quinine, the cinchona alkaloid quinidine is the antimalarial agent most widely used intravenously (46,49).…”

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Saccharomyces cerevisiae Multidrug Resistance Transporter Qdr2 Is Implicated in Potassium Uptake, Providing a Physiological Advantage to Quinidine-Stressed Cells

et al. 2007

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The QDR2 gene of Saccharomyces cerevisiae encodes a putative plasma membrane drug:H ؉ antiporter that confers resistance against quinidine, barban, bleomycin, and cisplatin. This work provides experimental evidence of defective K ؉ (Rb ؉ ) uptake in the absence of QDR2. The direct involvement of Qdr2p in K ؉ uptake is reinforced by the fact that increased K ؉ (Rb ؉ ) uptake due to QDR2 expression is independent of the Trk1p/Trk2p system. QDR2 expression confers a physiological advantage for the yeast cell during the onset of K ؉ limited growth, due either to a limiting level of K ؉ in the growth medium or to the presence of quinidine. This drug decreases the K ؉ uptake rate and K ؉ accumulation in the yeast cell, especially in the ⌬qdr2 mutant. Qdr2p also helps to sustain the decrease of intracellular pH in quinidine-stressed cells in growth medium at pH 5.5 by indirectly promoting H ؉ extrusion affected by the drug. The results are consistent with the hypothesis that Qdr2p may also couple K ؉ movement with substrate export, presumably with quinidine. Other clues to the biological role of QDR2 in the yeast cell come from two additional lines of experimental evidence. First, QDR2 transcription is activated under nitrogen (NH 4 ؉ ) limitation or when the auxotrophic strain examined enters stationary phase due to leucine limitation, this regulation being dependent on general amino acid control by Gcn4p. Second, the amino acid pool is higher in ⌬qdr2 cells than in wild-type cells, indicating that QDR2 expression is, directly or indirectly, involved in amino acid homeostasis.

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Novel target genes of the yeast regulator Pdr1p: a contribution of the TPO1 gene in resistance to quinidine and other drugs

Cited by 50 publications

References 29 publications

The Central Role of PDR1 in the Foundation of Yeast Drug Resistance

The Central Role of PDR1 in the Foundation of Yeast Drug Resistance

Yeast response and tolerance to polyamine toxicity involving the drug : H+ antiporter Qdr3 and the transcription factors Yap1 and Gcn4

Saccharomyces cerevisiae Multidrug Resistance Transporter Qdr2 Is Implicated in Potassium Uptake, Providing a Physiological Advantage to Quinidine-Stressed Cells

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